Process for obtaining pure polyalkylene glycol ethers



PROCESS FOR OBTAINING PURE POLYALKYLENE GLYCOL ETHERS Filed July 5, 1957 April 18, 1961 u. GEYER ET AL 5 Sheets-Sheet 2 NGE I ON.

ww uwe April 18, 1961 u. GEYER ETAL PROCESS FOR OBTAINING PURE POLYALKYLENE GLYCOL ETHERS Filed July 5, 1957 5 Sheets-Sheet 5 W ATTOR NE) I ON ULRICH GEYER MAX sP/LLM V ARNOLD STALDEIQ 506E TAc-3MANN l 00- m N v I DON 2 26 wt 5 3: E wocoE oulm mew- 52: 0 @290; 8.3 2: +0 32 'NdON l ONN United States Patent?) 2,980,737 PROCESS FOR OBTAINING PURE POLY- ALKYLENE GLYCOL ETHERS Ulrich Geyer, Binningen, Max Spillmann, Therwil," Therwil,

Arnold Stalder, Basel, and Eugen Tagmann, Switzerland, assignors to Ciba Pharmaceutical Products Inc., Summit, NJ.

Filed July 5, 1957, Ser. No. 670,182 Claims priority, application Switzerland July 4, 1956 4 Claims. (Cl. 260-616) This invention provides a process for obtaining individual pure polyalkylene glycols, more especially polyethylene glycols, monoethers and carboxylic acid esters thereof from mixtures of these compounds.

2,980,737 Patented Apr. 18, 1961 action such as a hydroxide of such a metal, the waterin which, for example, after hydrolysis with an excess of It is known that in the synthesis of polyalkylene gly- I cols or their monoalkyl ethers by alkoxylation there are obtained mixtures of compounds having difierent degrees of polymerization and molecular weights. For example, a commercially available polyethylene glycol having a mean molecular weight of 400 is composed of the following individual polyethylene glycols:

Attempts to split up such mixtures into their individual components by fractional distillation are beset withconsiderable practical difliculties. Even when highly efiicient fractionating columns and highly efficient reflux condiylic acid esters thereof which are capable of being distilled, andsplitting up the resulting ester mixture into its components by fractional distillation, and, if desired, -de'- acylating the individual acyl-compounds. Thus, it has been found that mixtures of the aforesaid esters, in contra-distinction to mixtures of the polyalkylene glycols or their monoethers, can be split up very advantageously.

This could not have been expected, because in the case of both types of mixtures the differences in the boiling points of the individual components are of the same order. Although the esterification usually results in raising the boiling points there is less risk of decomposition of the acyl-derivatives than of the polyalkylene glycols or their monoethers. As mixtures of esters to be subjected to the splitting operation there are advantageously used those of fatty acids of low molecular weight such as acetic acid or propio'nic acid. I The esterification and also the de-acylation, may be carried out by methods in themselves known. In working up the individual products, after hydrolysing the acylated product, for example, by means of an'alkali metal or alkaline earth metal compound of alkaline re- 7 an alkali metal hydroxide the clear aqueous hydrolysis 10 solution is so concentrated by evaporation that the free polyalkylene glycol or monoether thereof separates out, and is easily separated from the concentrated aqueous or dry inorganic residue by extraction with a solvent. As solvents there are especially suitable those which are immiscible with water and are incapable of dissolving the inorganic residue, such as benzene, toluene, chloroform etc. ,The individual polyalkylene glycols, their monoalky'l ethers or carboxylic acid esters having a well defined degree of polymerization and a definite molecular weight are useful as starting materials for making pharmaceutical preparations or as diluents or solvents, for example, also for pharmaceutical substances for example for the preparation of polethylene glycolesters of p-butylaminobenzoic acid, and are also useful as textile assistants.

The following examples illustrate the invention:

EXAMPLE 1 300 grams of a mixture consisting of equal parts of 'syntheticallyfprepared octa-, nonaand deca-ethylene glycol monomethyl ether are heated with 600 grams of acetic anhydride in the presence of 60 grams of pyridine for 5 hours at C. v The acetylation mixture is freed from excess of acetic anhydride and acetic acid under reduced pressure produced by a water jet pump, then distilled in a double tube column 35 centimeters high and 55 millimeters wide, which is provided with an inner tubular column 25 centimeters high and 35 millimeters wide, filled with McMahon saddle-shaped bodies 6 x 6 millimetres of non-rusting wire gauze having 950 meshes per square centimeter and held in position on both sides with York mesh steel gauze. The distillate formed by condensation of the vapour is drawn off from the space between the inner and outer tubes. The temperature equilibrium caused by the two concentrically arranged tubes results in practically adiabtic conditions in the inner column. The pressure and temperature are measured at thetop of the column. At that position the apparatus is connected through a condenser to a high vacuum unit. At a rate of distillation of 100-200 grams per hour and a reflux ratio of about 1:10 the fractionation represented in Fig. 1 of the accompanying drawings was obtained.

The individual well defined fractions of the monomethyl ethers of octa-, nonaand deca-ethylene glycol acetate were hydrolysedby boiling in 'a 2 N-solution of caustic soda, the hydrolysis mixture was concentrated by evaporation to a content of alkaline liquor of 20-30% by weight, and the hydrolysis products were isolated with toluene. By purifying the fractions by distillation under a high vacuum in a Claisen flask the pure octa-, nonaand deca-ethylene glycol monomethyl ethers 'were obtained. l

For the purpose of comparison a corresponding nonacetylated polyethylene glycol monomethyl ether mixture was fractionated under identical conditions of distillation. The result of the distillation'of the non-esterified mixture is shown in Fig. 1 for comparison with the corresponding acetate mixture.

As a'criterion of purity there was used, inter alia, the solidification point (SP) as being a very specific analytical characteristic. The physical data of the respective pure homologous ocmpounds are given in Table I.

Table 1 Com ound Free glycol Glycol acetate p HO-[GH,GH=]..OH CHiOOO[CH;CH,O1,CH,

Number of thoxy groups.n=- .8 9 8 9 10 Pro ertles: V

- oiling point, 0 1188- 210 200 @215 4235 under mm. pressure of mercury--- 10.08; -.-0. :0. 1 4 0. m 0 solidification point (SP), O '04. 14:6 4. 3:4 9. 2 Refractive index, 1115 5.- -1. 4580i .1. 4604 .1. 4610 1.4532 1:4556 1. 4570 Densltmdfi" .1. 089 .1095 v 1. 087 1. 093 1. 096 Molecular wei ht alculated? 426 5 470:5 514 6 i-iound 1 425 1 467.;6 511 1 l Onthebasls of the saponlficatlon'number- EXAMPLE '2 EXAMPLE 3 A polyethylene glycol monomethyl :etherzhavingamean molecular weight of 350 was heated-with 1.5 equivalents of acetic anhydride for 5 hours at C., and the excess of acetic anhydride and acetic acid'was distilled .off under reduced pressure. The-crude acetylation mixture was 'fractionally distilled. The iractiouboiling at 212-215 C. under 0.10 .mm. :pressure of mercury was identified as pure non-ethylene glycol .monomethyl ether acetate. After being hydrolysed at the boilfor 15 hours with 3 equivalents of 2 N-solution .oflcaustic soda, .-the

reaction :solution was concentrated-to a .finaltconcentrw none-ethylene glycol monomethyl ether isolated in this manner are as follows:

Boiling point 210 .C.(0.12 mnnpressure of .S.P, 142 C.

From non-acylated polyethylene :-glycol rmonomethyl "ether, which was distilled under analogous conditions for comparison, the fractions obtained-consisted of mixtures.

These fractions were evaluated with :respect 10 their content of non-ethylene glycol .monomethyl ether, as :described in Example 1, by .acetylation'followed by .frac- .tional distillation ofthe acetylated products. ThG'IGSUlllS of this distillation are shown in Table32.

From this data it will be seen thatxby this .fractional distillation the desired nona-ethylene glycolmono-methyl -ether is enriched merely infractions 3-6, :but could not be isolated in pure .form.

.200 grams :of :an .ordinary commercial:triethylenmglycol monomethyl;ether .wereheated with 1.5-equivalents of :acctic'anhydride for .5 .hours;at;100 C. .Atter-dis- .tilling ofi acetic. acid and the -excess; of. acetic anhydride, the crude product so obtained was fractionated under 11mm. pressure-of .mercury in a Podbielniak-Heligrid column 55 centimeters high and having a diameter of .l2.millimeters at arefluxratio of 1:50 and with a .fall in vapour pressure (.betweenthe top ofthecolummand the distillationtstill) .of .12 .centimeters glycol .column.

The quantity of distillate per hour amountedto 4 to 4.5 grams. The distillate yielded 27.5% of pure triethylene glycol monornethyl "ether acetate having the 'following physical properties. 'Boiling point 140.5 C.-(12 mm. pressure Hg) After hydrolysing this product lay-boiling 'itffor :5 hours with 3 equivalents of a3,N=soh1tion.of caustic soda and concentrating the hydrolysis mixture :to a concentration of alkaline liquor of.about.3.0% .by weight, the crude hydrolysis product was extracted with'chloror'orm. By .distillation in an ordinary .Claisen .flask there was-ob- .tained pure triethylene glycol monomethyl ether having the following properties:

Boilingpoint 126-127 C. (11mm. pressure-Hg) 1.4380 d 1.0481

:Table 2 Results of distillation of polyethylene glycol monomethylether having a mean molecular weight of 350] Distillation I Percent by v SP-lnterval, weight of 'Efl'ective Fraction mm. boiling degrees un -interval distillate content Pressure olnt, ,(addltlve) of l of egrees i mercury 46-200 l0 1. 4385-1. 4509 20. 0 0 200-207 -10 to 5 1. 4509-1. 4569 41. 6 0 207-211 --5 00 1. 45 1. 4572 59. 2 10. 6 211-247 01:0 6. 2 1. 4572-1. 4580 68. 5 19. 1

247 6.2 to 8. 5 '1. 4530-1. 4585 71. 8 25. 0 247-271 8 5 to'11.6 1.14585-1. 4605 89. 5 I 18. 5 271-273 11 6 to 12. 6 1. 46054.4606 95. 4 0

1 Nona-ethylene glycolmonomcthyl ether in. pereentegehy welghh' the corresponding acylated mixture when distilled under analogous conditions are shown in Fig. 2.

EXAMPLE 4 200 grams of a triethylene gylcol monomethyl ether of different origin from that used in Example 3 and acetylated in the manner described in that example, were distilled. The course of the distillation was compared with that of the non-acetylated triethylene glycol monomethyl ether. The fractional distillations were carried out in a Podbielniak-Heligrid column under the conditions described in Example 3. At a distillation rate of 4.5 to 7 grams per hour there were obtained, calculated on the molecular weights determined by refractive indices and hydrolysis or acetylation numbers, respectively, the following yields of pure products: 17.2% of triethylene glycol monomethyl ether and 56.9% of triethylene glycol monomethyl ether acetate, respectively.

The courses of these two distillations with respect to the molecular weights found are graphically represented in Fig. 3. The progression of boiling points and associated refractive indices and the molecular weights found are set out in Tables 3 and 4.

By hydrolysing the triethylene glycol monomethyl ether acetate in the manner described in Example 3 there was obtained pure triethylene glycol monomethyl ether in a yield of 49.2% calculated on the weight of the starting material.

Table 3 [Distillation of triethylene glycol monomethyl ether (n =1.4380; molwt.=164.2)]

Percent by Fraction Boiling point weight of 7m Mol. wt!

(11 mm. Hg) distillate found (additive) 1 67-88 6. 6 1. 4268 15. 4 1. 4380 97. 9 26. 1. 4402 126. 4 32. 8 1. 4402 38. 9 1. 4404 127. 8 43. 1. 4402 47. 1 1. 4402 124. 4 54.8 1. 4398 9 64.3 1. 4394 147.9 73. 9 1.4392 11 82. 5 1. 4392 156. 4 12 128.0 91.1 1. 4392 13 residue 93. 5

1 The molecular weights were calculated from the saponification or acetylation values found, on the assumption that only one acetylatable hydroxyl function was present in the molecule.

Table 4 Distillation of trlethylene glycol monometh l ether acetate (n =1.4320;

moi. Wt.=206.2) I

Percent by Fraction Boiling point weight of 1m" Mol. wt 1 (11 mm. Hg) distillate found (additive) residue 97. 9

The molecular weights were calculated from the saponiflcation or acetylation values found, on the assumption that only one acetylatable hydroxyl function was present in the molecule.

6 EXAMPLE 5 having a solidification point of 32 C. Molecular weight determination gave a molecular weight of 475.5 (calculated=470.54).

By hydrolysis in the manner described in Example '2 pure nona-ethylene glycol monomethyl ether was ob; tained in a yield of 8.82% calculated on the starting material used.

What is claimed is:

1. A process for obtaining individual polyethylene glycol mono-lower alkyl ethers which comprises esterifying a mixture of polyethylene glycol mono-lower alkyl ethers with acetic acid, subjecting the resulting mixture of esters to fractional distillatiion to separate the individual esters and deacetylating the separated individual esters by hydrolysis.

2. A process for obtaining polyethylene glycol monolower alkyl ethers, which comprises esterifying a mixture of polyethylene glycol mono-lower alkyl ethers with a lower fatty acid, subjecting the resulting mixture of esters to fractional distillation to separate the individual esters and deacylating a resulting individual ester by hydrolysis.

3. A process as claimed in claim 2 wherein a mixture of polyethylene glycol monomethyl ethers is used as starting material.

4. A process as claimed in claim 2 wherein a mixture of polyethylene glycol monomethyl ethers containing nonaethylene glycol monomethylether is used as starting material.

References Cited in the file of this patent UNITED STATES PATENTS Reid Jan. 21, 1941 Matter Aug. 2, 1955 OTHER REFERENCES UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 238mm? April 18 1961 Ulrich Geyer et al0 It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1,, in the table column l line 9 thereof for "Dodecaethyleneglycol"- read Dodeca-ethylene glycol column 3 lines 25 and 50 for "non-ethylene" read nona== ethylene column 6 line 43,, for "nonaethylene" read none-ethylene Signed and sealed this 28th day of November 1961o (SEAL) Attest:

ERNEST W. SWIDER Attesting Officer DAVID L. LADD Commissioner of Patents USCOMM-DC 

1. A PROCESS FOR OBTAINING INDIVIDUAL POLYETHYLENE GLYCOL MONO-LOWER ALKYL ETHERS WHICH COMPRISES ESTERIFYING A MIXTURE OF POLYETHYLENE GLYCOL MONO-LOWER ALKYL ETHERS WITH ACETIC ACID, SUBJECTING THE RESULTING MIXTURE OF ESTERS TO FRACTIONAL DISTILLATION TO SEPARATE THE INDIVIDUAL ESTERS AND DEACETYLATING THE SEPARATED INDIVIDUAL ESTERS BY HYDROLYSIS. 